Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[C:16][CH2:17][OH:18])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)C.O=[Pt]=O.O>[C:1]([O:5][C:6](=[O:19])[N:7]([C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:13][CH2:14]1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C#CCO)CC1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCO)CC1

Procedure:
A suspension of 3.4 g (12.72 mmol) of trans-[4-(3-Hydroxy-prop-1-ynyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester in 125 ml ethanol and 810 mg of PtO2.H2O was hydrogenated (1 atm) for 7 h. The reaction was filtered (Celite) and evaporated to give 3.5 g (quantitative) of trans-[4-(3-Hydroxy-propyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester, MS: 271 (MH).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([NH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Product: CCCCNC(=O)NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1

Procedure:
2-Amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and butyl isocyanate were treated in the same manner as in Example 29 to obtain 2-(butylcarbamoyl) amino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1>[C:14]1([N:20]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:21]([C:22]2[CH:27]=[CH:26][C:25]3[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:30][C:24]=3[CH:23]=2)=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccc1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1

Procedure:
6.17 g (0.035 mol) of N-(4-cyanophenyl)glycine and 5.68 g (0.035 mol) of N,N′-carbonyldiimidazole were refluxed in 300 mL of tetrahydrofuran for 30 minutes, then 10.6 g (0.032 mol) of 3-amino-4-methylaminobenzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide were added, and the mixture was refluxed for a further five hours. Then the solvent was distilled off in vacuo, the residue was dissolved in 150 mL of glacial acetic acid and refluxed for one hour. Then the glacial acetic acid was distilled off in vacuo, the residue was dissolved in about 300 mL of dichloromethane, the solution was washed twice with about 150 mL water and then dried over sodium sulfate. After evaporation of the solvent, the crude product thus obtained was purified by column chromatography (800 g silica gel; eluant: dichloromethane with 1-2% ethanol). Yield: 8.5 g (57% of theory); Rf value: 0.51 (silica gel; dichloromethane/ethanol=19:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[N:15][C:16]([NH2:20])=[N:17][CH:18]=2)[N:13]([CH3:21])[N:12]=1.[Cl:22]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(#N)C>[Cl:22][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:11]2[C:19]3[C:14](=[N:15][C:16]([NH2:20])=[N:17][CH:18]=3)[N:13]([CH3:21])[N:12]=2)[CH:5]=1
Reactant: COc1ccc(-c2nn(C)c3nc(N)ncc23)c(OC)c1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CC#N
Product: COc1cc(OC)c(-c2nn(C)c3nc(N)ncc23)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-(2,4-Dimethoxy-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Example 89) is suspended in acetonitrile (10 ml), trichloroisocyanuric acid (0.021 g, 0.09 mmol) is added and the reaction mixture is stirred for 1.5 hours at room temperature then stood overnight. The solvents are removed in vacuo, the residue is dissolved in EtOAc, washed with water and brine, dried over MgSO4, filtered, concentrated in vacuo and dried under vacuum (45° C.) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[N:24][N:23]=[N:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:19][C:17]3[N:18]=[C:14]([CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[S:15][CH:16]=3)=[CH:28][CH:27]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Reactant: Oc1ccc(-n2cnnn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1

Procedure:
A mixture of 4-(4-chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (549 mg), 4-tetrazol-1-yl-phenol (270 mg), Cs2CO3 (890 mg) in acetonitrile was heated under reflux overnight. After cooling, the reaction mixture was filtered through a pad of celite, concentrated in vacuo. Purification by chromatography (40-100% EtOAc/Hexanes) gave the desired product as a white solid. 1H NMR (CDCl3): δ 8.01 (1H, s), 7.61 (2H, d, J=8.8 Hz), 7.25 (1H, s), 7.15 (2H, d, J=8.8 Hz), 5.22 (2H, s), 4.2 (2H, br), 3.17 (1H, m), 2.87 (2H, m), 2.11 (2H, m), 1.73 (2H, m), 1.46 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1F)[CH:13]=[O:14]>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH:13]=[O:14]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1cccc(F)c1
Product: O=Cc1ccc(Oc2cccc(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-fluorophenol and 3,4-difluorobenzaldehyde.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:61])([CH3:60])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[CH:53]=2)[C:47]1=[O:59])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)c1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(C)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.8 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 66A (0.023 g, 0.076 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol) and the mixture was stirred at 25° C. for 2 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.013 g, 42% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.89 (m, 9 H), 1.47 (m, 2 H), 2.28 (s, 3 H), 2.39 (m, 1 H), 2.78 (m, 6 H), 3.22 (m, 1 H), 3.54 (m, 4 H), 3.84 (d, J=9.93 Hz, 1 H), 3.93 (m, 1 H), 4.04 (s, 1 H), 4.25 (m, 3 H), 4.45 (d, J=6.99 Hz, 1 H), 6.88 (d, J=9.93 Hz, 1 H), 7.05 (m, 7 H), 7.24 (m, 4 H), 7.32 (m, 1 H), 7.54 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH2:1]([C@H:3]1[O:11][C@H:10]2[C@H:6]([N:7]=[C:8]([N:12]([CH3:14])[CH3:13])[S:9]2)[C@@H:5]([O:15]CC2C=CC(OC)=CC=2)[C@@H:4]1[O:25]CC1C=CC(OC)=CC=1)[CH3:2].C(O)(C(F)(F)F)=O.[NH4+].[OH-]>ClCCl>[CH3:14][N:12]([CH3:13])[C:8]1[S:9][C@H:10]2[O:11][C@H:3]([CH2:1][CH3:2])[C@@H:4]([OH:25])[C@H:5]([OH:15])[C@H:6]2[N:7]=1
Reactant: CC[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2[C@@H](O)[C@@H]1O
Reaction time: 0.17 h
Yield: 28.9 %

Procedure:
A solution of above crude product 41 (260 mg, purity 54% by LC-MS) in dichloromethane (10 mL) was treated with TFA (1 mL) for 4 hours at room temperature. The solution was adjusted to pH at 8 with NH4OH, and then condensed to give a crude product, which was purified by Prep-HPLC with the following conditions (Agilent 1200 prep HPLC: Column, SunFire Prep C18,19*50 mm 5 um; mobile phase, WATER with 0.03% NH4OH and CH3CN (10% CH3CN up to 45% in 10 min; Detector, UV 220 nm) to provide compound 42 (Example 6) as a white solid (38 mg). (ES, m/z): [M+H]+ 247.0. 1H NMR (300 MHz, D2O) δ 6.18-6.21 (d, J=6.6 Hz, 1H), 4.09-4.13 (t, J=6.0 Hz, 1H), 3.91-3.94 (t, J=4.8 Hz, 1H), 3.42-3.44 (m, 2H), 2.92 (s, 6H), 1.69-1.77 (m, 1H), 1.40-1.50 (m, 1H), 0.84-0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C1(C)C=CC(S(O)(=O)=[O:15])=CC=1.[C:19]1([CH3:26])[CH:24]=CC=C(C)[CH:20]=1>>[CH3:6][C:2]1([CH3:7])[O:1][C:20](=[O:15])[C:19]([CH3:26])([CH3:24])[O:5][C:3]1=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: Cc1cccc(C)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(C)OC(=O)C(C)(C)OC1=O

Procedure:
Crude tetramethyl glycolide was prepared by direct liquid phase synthesis from 2-hydroxy-2-methylpropionic acid using m-xylene as the solvent and p-toluene sulfonic acid as the catalyst. The mixture was refluxed using a Dean-Stark tube to remove water.
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.C(I)I.[F:16][CH:17]([F:31])[C:18]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH2:19].C(Cl)Cl>C(Cl)Cl>[F:31][CH:17]([F:16])[C:18]1([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:24])[CH3:23])[CH2:2][CH2:19]1
Reactant: C=C(O[Si](C(C)C)(C(C)C)C(C)C)C(F)F
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ICI
Product: CC(C)[Si](OC1(C(F)F)CC1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask (fitted with glass inlet and outlet) was charged with 60 ml DCM followed by Et2Zn (60 mmol, 60 ml, 1 M in hexane) and cooled to 0° C. TFA (60 mmol, 4.62 ml dissolved in 30 ml DCM) was slowly added to the stirring solution. The reaction was stirred for 20 minutes, followed by addition of CH2I2 (60 mmol, 4.83 ml dissolved in 20 ml DCM) and 20 minutes further stirring. At this point, (1-Difluoromethyl-vinyloxy)-triisopropyl-silane DCM (11.98 mmol, 3 g dissolved in 30 mL) was added and the mixture warmed to rt and stirred for 1 hour. The reaction was then quenched with 1 N HCl and water and extracted two times with hexane. The combined organics were washed with saturated NaHCO3 and dried over sodium sulfate and concentrated, providing (1-difluoromethyl-cyclopropoxy)-triisopropyl-silane which was used crude in the next reaction.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][NH:9][CH2:8][CH2:7]2.S(Cl)([Cl:19])(=O)=O>C(O)(=O)C>[ClH:19].[Cl:1][C:5]1[C:4]([O:3][CH3:2])=[C:13]([O:14][CH3:15])[C:12]([Cl:19])=[C:11]2[C:6]=1[CH2:7][CH2:8][NH:9][CH2:10]2
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(Cl)c2c(c(Cl)c1OC)CNCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (200 mg, 0.870 mmol) was suspended in glacial acetic acid (5 mL) and sulphuryl chloride (154 μL, 1.92 mmol) was added slowly. The resulting mixture was stirred at room temperature for 3 hours and then evaporated to give the title compound (quant) as a yellowish mass.
Reaction SMILES: [C:1]([NH:4][OH:5])(=O)[CH3:2].CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[CH:19]C=[C:17]([S:21]([C:24]2[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:14]=1C#N.O.C[N:41](C)C=O>>[F:38][C:35]1[CH:34]=[CH:33][C:32](/[CH:31]=[CH:30]/[C:27]2[CH:28]=[CH:29][C:24]([S:21]([C:17]3[C:2]4[C:1]([NH2:41])=[N:4][O:5][C:19]=4[CH:20]=[CH:13][CH:14]=3)(=[O:22])=[O:23])=[CH:25][CH:26]=2)=[CH:37][CH:36]=1
Reactant: N#Cc1c(F)cccc1S(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Reactant: CC(=O)NO
Reactant: CN(C)C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: Nc1noc2cccc(S(=O)(=O)c3ccc(/C=C/c4ccc(F)cc4)cc3)c12
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A solution of acetohydroxamic acid (75 mg, 1 mmol) in N,N-dimethylformamide was treated at room temperature with potassium tert-butoxide and stirred for 30 minutes. 2-fluoro-6-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)benzonitrile (Example 112, 100 mg, 0.26 mmol) was added and the reaction stirred for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine (×5), dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica to give the title compound (30 mg, 29%). δH (500 MHz, CDCl3): 8.00 (2H, d, J=8.6 Hz), 7.92 (1H, dd, J=7.3, 0.85 Hz), 7.68–7.58 (4H, m), 7.49–7.46 (2H, m), 7.15 (1H, d, J=16.3 Hz), 7.06 (2H, t, J=8.6 Hz), 6.98 (1H, d, J=16.3 Hz).
Reaction SMILES: CC(C(N)=O)[C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([F:12])=[C:5]([Cl:13])[CH:4]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[CH2:39]([NH2:47])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[N:48]1C=C[CH:51]=[CH:50][CH:49]=1>C(OCC)(=O)C>[Cl:13][C:5]1[CH:4]=[C:3]2[C:8]([C:9](=[O:11])[N:47]([CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:49]([CH2:50][CH3:51])=[N:48]2)=[CH:7][C:6]=1[F:12]
Reactant: NCCc1ccccc1
Reactant: CC(C(N)=O)c1cc(Cl)c(F)cc1C(=O)O
Reactant: c1ccncc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CCc1nc2cc(Cl)c(F)cc2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.2 %

Procedure:
The crude solid (3 g) from step 3 above mixed with triphenyl phosphite (4 mL, 14.81 mmol) in pyridine (15 mL) was stirred at rt for 4 h. The mixture was added with phenethylamine (1.55 mL, 12.18 mmol), irradiated with microwave 250 W to refluxing for 15 min. The mixture was diluted with ethyl acetate (50 mL), washed with water (2×50 mL). The ethyl acetated solution was mixed with water (50 mL) and kept at rt to give solid form. The solution was filtered to give yellow solid title compound (1.1 g, 27.2%). mp=150-152° C. (recrystallized from ethyl acetate); 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.2 Hz, 3H, CH3), 2.76 (q, J=7.2 Hz, 2H, CH2), 2.93 (br t, J=7.6 Hz, 2H, CH2), 4.19 (br t, J=7.6 Hz, 2H, CH2), 7.20-7.31 (m, 5H, ArH), 7.80 (d, J=6.4 Hz, 1H, ArH), 7.91 (d, J=8.8 Hz, 1H, ArH), 13C NMR (100 MHz, DMSO-d6) δ 10.6, 26.9, 33.5, 44.8, 112.2, 112.4, 119.8, 119.9, 126.6, 126.8, 127.0, 128.5, 128.7, 128.8, 138.0, 144.1, 153.6, 156.1, 158.9, 160.0; Anal. (C18H16ClFN2O) C, H, N. Calcd: 65.36, 4.88, 8.47. Found: 65.09, 4.77, 8.50.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=O)=[O:21].[CH2:31]1[C:39]2[C:34](=[CH:35]C=CC=2)[CH2:33][N:32]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:33][CH:34]([CH3:35])[CH2:39][CH2:31][NH:32][C:28](=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][NH:22][C:20]([N:12]1[CH2:11][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:21]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)CCCCCNC(=O)N1Cc2ccccc2C1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)CCCCCNC(=O)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 3-methylbutan-1-amine for 3-phenylpropan-1-amine and 6-[(1,3-dihydro-2H-isoindol-2-ylcarbonyl)amino]hexanoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.64-7.69 (m, 1H), 7.24-7.34 (m, 4H), 6.26 (t, J=5.5 Hz, 1H), 4.57 (s, 4H), 2.99-3.10 (m, 4H), 2.03 (t, J=7.3 Hz, 2H), 1.41-1.59 (m, 5H), 1.21-1.30 (m, 4H), 0.84 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 346 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]([CH:11]=O)[CH2:9][CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)=O.C(O)(=O)C.[CH3:31][NH2:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[CH2:20]([C:5]12[C:3](=[O:2])[N:32]([CH3:31])[CH2:11][CH:10]1[CH2:9][CH2:8][N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6]2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1C=O
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CC2CCN(Cc3ccccc3)CC2(Cc2ccccc2)C1=O
Temperature: 70 °C

Procedure:
To a solution of the compound of Example 200, Step C (0.210 g, 0.60 mmol) in dichloroethane (5 mL) in a resealable tube was added acetic acid (0.188 mL, 3.28 mmol), methyl amine (2.0 M in MeOH, 1.64 mL, 3.28 mmol) and NaB(OAc)3H (0.951 g, 4.48 mmol), the tube was sealed and the reaction mixture was heated to 70° C. for 30 h. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate solution. The organic layer was removed and the aqueous layer was washed twice with CH2Cl2, the combined organic layers were washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 5-20% EtOAc/CH2Cl2 as the eluant afforded the less polar isomer of Example 200, Step D (0.034 g) as well as the more polar isomer (0.046 g). Example 200, Step D less polar isomer. +APcl MS (M+1)+ 335; 1H NMR (400 MHz, CDCl3) δ: 7.03-7.37 (arom, series of m, 10 H), 3.54 (m, 2H), 3.24 (m, 1H), 2.70 (s, 3H). More polar isomer: +APcl MS (M+1)+ 335; 1H NMR (400 MHz, CDCl3) δ: 7.15-7.33 (arom, series of m, 10 H), 3.59 (d, 1H), 3.43 (d, 1H), 2.74 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:13]=2[CH:29]([CH3:31])[CH3:30])=[O:11])[CH:5]=[N:6][CH:7]=1.[CH:32]1(I)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([O:21][C:17]2[CH:16]=[C:15]3[C:20]([C:12]([C:10]([NH:9][CH2:8][C:4]4[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[O:11])=[C:13]([CH:29]([CH3:31])[CH3:30])[N:14]3[CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CC(C)c1c(C(=O)NCc2cncc(F)c2)c2ccc(O)cc2n1Cc1cccnc1
Reactant: IC1CCCC1
Product: CC(C)c1c(C(=O)NCc2cncc(F)c2)c2ccc(OC3CCCC3)cc2n1Cc1cccnc1

Procedure:
The title compound was prepared from N-((5-fluoropyridin-3-yl)methyl)-6-hydroxy-2-isopropyl-1-(pyridin-3-ylmethyl)-1H-indole-3-carboxamide (Compound 162) and cyclopentyl iodide by General Procedure N.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]([C:9]1[S:10][CH:11]=[C:12]([Br:14])[CH:13]=1)=[O:8]>OS(O)(=O)=O>[CH3:5][O:6][C:7]([C:9]1[S:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]([Br:14])[CH:13]=1)=[O:8]
Reactant: COC(=O)c1cc(Br)cs1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reaction time: 0.5 h

Procedure:
The nitrating mixture (HNO3 d=1.42, 2 mL; concentrated H2SO4, 6 mL) was slowly added with stirring, at −5 to −10° C., to 4-Bromothiophene-2-carboxylic acid methyl ester (3 g, 13.57 mmol) dissolved in concentrated H2SO4 (10 mL). After being kept at −5 to −10° C. for 30 min. the mixture was poured over crushed ice. The solid precipitate was separated by filtration and washed with water and dried over P2O5 to give 3.7 g of 4-bromo-5-nitrothiophene-2-carboxylic acid methyl ester as a tan solid, which was used in the next step without further purification.
Reaction SMILES: FC1C(C(O)=O)=C([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)C(C)=CC=1.[F:17][C:18]1[C:19]([CH3:28])=[CH:20][C:21](I)=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]>>[F:17][C:18]1[C:19]([CH3:28])=[CH:20][C:21]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24]
Reactant: Cc1cc(I)c(C(=O)O)cc1F
Reactant: Cc1ccc(F)c(C(=O)O)c1-n1nccn1
Product: Cc1cc(-n2nccn2)c(C(=O)O)cc1F

Procedure:
The title compound was prepared following the same general protocol as described for 6-fluoro-3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid in Example A352 using 5-fluoro-2-iodo-4-methylbenzoic acid. MS (ESI) 222 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:13][O:14][C:15](=[O:26])[CH:16]([NH2:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[CH3:13][O:14][C:15](=[O:26])[C@@H:16]([NH:25][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[OH:11])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1
Reactant: COC(=O)C(N)Cc1ccc(Br)cc1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1O
Yield: 50 %

Procedure:
5-Chloro-2-hydroxy-benzoic acid (2.5 g, 28.97 mmol) was coupled with 2-amino-3-(4-bromo-phenyl)-propionic acid methyl ester hydrochloride (4.26 g, 28.96 mmol) with HBTU (6.59 g, 34.76 mmol) and diisopropylethylamine (8 ml, 86.91 mmol) as per general procedure A to yield the corresponding 3-(4-Bromo-phenyl)-(2S)-(5-chloro-2-hydroxy-benzoylamino)-propionic acid methyl ester in 50% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[I:29]I.O>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]3[C:20]([C:21]=2[I:29])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: II
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)cc2ccccc21
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3=O)c(I)c2ccccc21
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 81.5 %

Procedure:
3-Amino-6-[1-(tert-butoxycarbonyl)indol-2-yl]phtalimide (300 mg, 0.795 mmol) was dissolved in ethanol (21 mL), and the solution was added with iodine (242 mg, 0.954 mmol) and silver sulfate (248 mg, 0.795 mmol), followed by stirring at room temperature for 1.3 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by slurry using chloroform to obtain 3-amino-6-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]phtalimide (326 mg, yield 82%).